Receptor Recognition of and Immune Intracellular Pathways for Veillonella parvula Lipopolysaccharide

ABSTRACT Veillonella parvula is an anaerobic gram-negative coccus that is part of the normal flora of the animal and human mouth and gastrointestinal and genitourinary tracts. Oral V. parvula is involved in the development of early periodontal disease as well as different types of serious infections. Present data on molecular mechanisms responsible for innate immune response against Veillonella are very scanty. The aim of this study was to investigate the Toll-like receptor (TLR) pathways responsible for V. parvula lipopolysaccharide (LPS) and to identify the intracellular pathways induced by this recognition. V. parvula LPS stimulated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) release in human peripheral blood mononuclear cells (PBMC) in a dose-dependent manner. Pretreatment of cells with a TLR4 antagonist significantly reduced TNF-α and IL-6 production in PBMC stimulated with either Veillonella or Escherichia coli LPS. However, V. parvula LPS was 10- to 100-fold less active than E. coli LPS for cytokine induction. TNF-α, IL-1β, IL-6, and IL-10 were released in wild-type and TLR2−/−, but not TLR4−/−, mouse macrophage cultures. V. parvula LPS was able to activate the human PBMC p38 mitogen-activated protein kinase (MAPK). A specific p38 MAPK inhibitor strongly inhibited V. parvula LPS-induced TNF-α, IL-1β, IL-6, and IL-10. In conclusion, V. parvula LPS is able to induce cytokine production in both human and murine in vitro models, although it is less effective than Enterobacteriaceae LPS. V. parvula LPS-stimulated cytokine induction, as well as p38 MAPK activation, are TLR4-dependent features.

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Candida tropicalis induces pro-inflammatory cytokine production, NF-κB and MAPKs pathways regulation, and dectin-1 activation

Canadian Journal of Microbiology ◽

10.1139/cjm-2017-0559 ◽

2018 ◽

Vol 64 (12) ◽

pp. 937-944 ◽

Cited By ~ 2

Author(s):

Zhimin Duan ◽

Qing Chen ◽

Rong Zeng ◽

Leilei Du ◽

Caixia Liu ◽

...

Keyword(s):

Signaling Pathways ◽

Inflammatory Cytokine ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Mapk Signaling ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Downstream Signaling ◽

Tnf Α ◽

Mitogen Activated Protein

The prevalence of Candida infection induced by non-albicans Candida (NAC) species is increasing. However, as a common NAC species, C. tropicalis has received much less study in terms of host immunity than C. albicans has. In this study, we evaluated the pro-inflammatory cytokine responses evoked by C. tropicalis and determined whether dectin-1 and downstream NF-κB and mitogen-activated protein kinases (MAPKs) signaling pathways played roles in inflammation in human peripheral blood mononuclear cells (PBMCs) and THP-1 macrophage-like cells. Exposure of PBMCs and THP-1 macrophage-like cells to C. tropicalis led to the enhanced gene expression and secretion of TNF-α and IL-6 in a time- and dose-dependent manner. THP-1 macrophage-like cells being challenged by C. tropicalis resulted in the activation of the NF-κB, p38, and ERK1/2 MAPK signaling pathways. We also found that the expression of dectin-1 was increased with C. tropicalis treatment. These data reveal that dectin-1 may play a role in sensing the inflammation response induced by C. tropicalis and that NF-κB and MAPK are involved in the downstream signaling pathways in macrophages.

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Dipyridamole decreases inflammatory metalloproteinase-9 expression and release by human monocytes

Thrombosis and Haemostasis ◽

10.1160/th12-05-0326 ◽

2013 ◽

Vol 109 (02) ◽

pp. 280-289 ◽

Cited By ~ 10

Author(s):

Maria Annunziata Carluccio ◽

Mariangela Pellegrino ◽

Nadia Calabriso ◽

Carlo Storelli ◽

Giuseppe Martines ◽

...

Keyword(s):

P38 Mapk ◽

Mononuclear Cells ◽

Nuclear Translocation ◽

Human Peripheral Blood ◽

Antiplatelet Agent ◽

Guanosine Monophosphate ◽

Human Monocytes ◽

Peripheral Blood Mononuclear ◽

Tnf Α ◽

Anti Inflammatory

SummaryMatrix metalloproteinase (MMP)-9 plays an important role in stroke by accelerating matrix degradation, disrupting the blood-brain barrier and increasing infarct size. Dipyridamole is an antiplatelet agent with recognised benefits in ischaemic stroke prevention. In addition to its antiplatelet properties, recent studies have reported that dipyridamole also features anti-inflammatory and anti-oxidant properties. We therefore investigated whether dipyridamole can ameliorate the proinflammatory profile of human monocytes, a source of MMP-9 in stroke, in terms of regulation of MMP-9 activity and expression, and explored underlying mechanisms. Human peripheral blood mononuclear cells (PBMC) and U937 cells were treated with increasing concentrations of dipyridamole (up to 10 µg/ml) for 60 minutes before stimulation with tumour necrosis factor (TNF)-α or phorbol myristate acetate (PMA). Exposure of PBMC and U937 to dipyridamole reduced TNF-α- and PMA-induced MMP-9 activity and protein release as well as MMP-9 mRNA, without significantly affecting the release of TIMP-1. This inhibitory effect was independent of dipyridamole-induced cyclic adeno-sine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) increase. Correspondingly, dipyridamole also significantly inhibited TNF-α-induced nuclear factor (NF)-κB activation and nuclear translocation of the p65 NF-κB subunit through a mechanism involving the inhibition of IkBα degradation and p38 MAPK activation. In conclusion, dipyridamole, at therapeutically achievable concentrations, reduces the expression and release of MMP-9 through a mechanism involving p38 MAPK and NF-κB inhibition. These results indicate that dipyridamole exerts anti-inflammatory properties in human monocytes that may favourably contribute to its actions in the secondary prevention of stroke, independent of its antiplatelet properties.

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Effect of Moxifloxacin on Production of Proinflammatory Cytokines from Human Peripheral Blood Mononuclear Cells

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.12.3704-3707.2003 ◽

2003 ◽

Vol 47 (12) ◽

pp. 3704-3707 ◽

Cited By ~ 27

Author(s):

Jung-Hyun Choi ◽

Min-Jin Song ◽

Seung-Han Kim ◽

Su-Mi Choi ◽

Dong-Gun Lee ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Tnf Α ◽

Blood Mononuclear Cells

ABSTRACT The effects of moxifloxacin, a new methoxyfluoroquinolone, on the production of proinflammatory cytokines from human peripheral blood mononuclear cells (PBMCs) were evaluated. Moxifloxacin inhibited the production of tumor necrosis factor alpha (TNF-α) and/or interleukin-6 (IL-6) by PBMCs stimulated with lipopolysaccharide (LPS), lipoteichoic acid (LTA), and heat-killed bacteria in a concentration-dependent manner without cytotoxic effects. The addition of moxifloxacin reduced the population of cells positive for CD-14 and TNF-α and for CD-14 and IL-6 among the LPS- or LTA-stimulated PBMCs. By Western blot analysis, moxifloxacin pretreatment reduced the degradation of IκBα in LPS-stimulated PBMCs. In conclusion, moxifloxacin could interfere with NF-κB activation by inhibiting the degradation of IκBα and reduce the levels of production of proinflammatory cytokines.

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NCS 613 exhibits anti-inflammatory effects on PBMCs from lupus patients by inhibiting p38 MAPK and NF-κB signalling pathways while reducing proinflammatory cytokine production

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2012-0233 ◽

2013 ◽

Vol 91 (5) ◽

pp. 353-361 ◽

Cited By ~ 12

Author(s):

Issaka Yougbaré ◽

Gilles Boire ◽

Michelle Roy ◽

Claire Lugnier ◽

Éric Rouseau

Keyword(s):

P38 Mapk ◽

Lupus Erythematosus ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Pde4 Inhibitor ◽

Human Pbmcs ◽

Peripheral Blood Mononuclear ◽

Healthy Donors ◽

Tnf Α ◽

Anti Inflammatory

Systemic lupus erythematosus (SLE) is a polymorphic and multigenic autoimmune disease that evolves into progressive and chronic inflammation of multiple joints and organs. Phosphorylation and activation of p38 MAPK, along with the resulting overproduction of interleukin (IL)-1β, IL-6, and tumour necrosis factor (TNF)-α is a hallmark of inflammatory disorders. Here, we investigated the anti-inflammatory pathway modulated by NCS 613, a specific PDE4 inhibitor, on human peripheral blood mononuclear cells (PBMCs) from 5 healthy donors and 12 SLE patients. PDE4 subtypes, p38 MAPK, and IκBα protein levels were analyzed by Western blot, while NF-κB and PDE4B immunostaining was assessed in control and lipopolysaccharide (LPS) -pretreated PBMCs. Proinflammatory cytokines were quantified by ELISA, while IL-1β mRNA was resolved by RT–qPCR. NCS 613 treatment decreased PDE4B and upregulated PDE4C in human PBMCs from healthy donors and SLE patients. LPS stimulation increased p38 MAPK phosphorylation and NF-κB translocation to the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restored IκBα detection levels in human PBMCs from both healthy donors and SLE patients. This compound also abolished LPS-induced inflammation in PBMCs by reducing IL-6, IL-8, and TNF-α cytokines. NCS 613 is a small molecule displaying anti-inflammatory properties that may provide an alternative or complementary strategy for SLE management.

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Stimulation of production of prostaglandin E in gingival cells exposed to products of human blood mononuclear cells

Biochemical Journal ◽

10.1042/bj1980391 ◽

1981 ◽

Vol 198 (2) ◽

pp. 391-396 ◽

Cited By ~ 16

Author(s):

S M D'Souza ◽

D J Englis ◽

A Clark ◽

R G Russell

Keyword(s):

Mononuclear Cell ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Gingival Tissue ◽

Prostaglandin E ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells ◽

Gingival Cells ◽

Stimulation Of

1. Supernatant media from cultures of unstimulated human peripheral blood mononuclear cells contained one or more factors that increased by several hundred-fold the production of prostaglandin E by fibroblast-like cells derived from both inflamed and normal human gingival tissue. 2. This stimulation occurred in a dose-dependent manner and was completely inhibited by 14 microM-indomethacin. 3. Responsiveness to the factor declined as the age of the cell culture increased. 4. An increase in prostaglandin E production was first observed after a 2h exposure to the mononuclear cell factor(s) and could be prevented by cycloheximide. 5. Brief exposure (0.5 and 1.0 h) to mononuclear cell factor did not increase prostaglandin E production by the cells in a subsequent 72 h incubation in the absence of mononuclear cell factor. 6. Addition of arachidonate (10 microM and 15 microM) further enhanced stimulation of prostaglandin E production in response to mononuclear cell factor. 7. The stimulatory activity was resistant to digestion by trypsin, but was heat-labile, so that only 17% remained after treatment at 56 degrees C for 30 min.

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Activation of Selective Transcription Factors and Cytokines by Water-Soluble Extract from Lentinus lepideus

Experimental Biology and Medicine ◽

10.1177/153537020322800615 ◽

2003 ◽

Vol 228 (6) ◽

pp. 749-758 ◽

Cited By ~ 26

Author(s):

Mirim Jin ◽

Hyung Jin Jung ◽

Jeong June Choi ◽

Hyang Jeon ◽

Jin Hwan Oh ◽

...

Keyword(s):

Mononuclear Cells ◽

Human Peripheral Blood ◽

Post Treatment ◽

Water Soluble ◽

Dependent Manner ◽

Soluble Extract ◽

Transient Transfection Assay ◽

Gm Csf ◽

Tnf Α ◽

Water Soluble Extract

We isolated a water-soluble extract, PG101, from cultured mycelia of Lentinus lepideus. Treatment of human peripheral blood mononuclear cells (PBMCs) with PG101 increased levels of TNF-α, IL-1β, IL-10, and IL-12 by 100- to 1000-fold, whereas GM-CSF and IL-18 were activated by an order of magnitude. On the contrary, IFN-γ and IL-4 were not affected. The response to PG101 occurred in a dose- and time-dependent manner. From the human PBMCs treated with PG101, TNF-α was a first cytokine to be activated, detectable at 2 hr post-treatment followed by IL-1β at 6 hr post-treatment. IL-12 and IL-10 were the next to follow. GM-CSF and IL-18 both showed significant increases 24 hr after treatment. When PBMCs were sorted into various cell types, monocyte/macrophages, but not T and B cells, were the major target cell type responsive to PG101. Consistent with this result, the profile of cytokine expression upon PG101 treatment was comparable between PBMCs and a human promonocytic cell line (U937), whereas cell lines of T cell and myeloid origins did not respond to PG101. Data from a transient transfection assay involving specific reporter plasmids indicated that cellular transcription factor such as NF-κB, but not AP-1, was highly activated by PG101. Results from a gel retardation assay and the experiment involving a specific NF-κB inhibitor confirmed the involvement of NF-κB. Despite its significant biological effect on various cytokines, PG101 remained nontoxic in both rats and PBMCs even at a biological concentration approximately 20 times greater. PG101 demonstrates great potential as a therapeutic immune modulator.

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Immunoglobulin A1 Protease, an Exoenzyme of Pathogenic Neisseriae, Is a Potent Inducer of Proinflammatory Cytokines

Journal of Experimental Medicine ◽

10.1084/jem.190.8.1049 ◽

1999 ◽

Vol 190 (8) ◽

pp. 1049-1058 ◽

Cited By ~ 52

Author(s):

Dirk R. Lorenzen ◽

Frank Düx ◽

Uwe Wölk ◽

Anastasios Tsirpouchtsidis ◽

Gaby Haas ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Mononuclear Cells ◽

Native Form ◽

Peripheral Blood Mononuclear ◽

Potent Inducer ◽

Cytokine Induction ◽

Regulatory Cytokine ◽

Iga1 Protease ◽

Tnf Α ◽

Necrosis Factor

A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-α and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.

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Leishmania (Viannia) braziliensis amastigotes induces the expression of TNFα and IL-10 by human peripheral blood mononuclear cells in vitro in a TLR4-dependent manner

Cytokine ◽

10.1016/j.cyto.2016.09.009 ◽

2016 ◽

Vol 88 ◽

pp. 184-192 ◽

Cited By ~ 13

Author(s):

Hélio Galdino ◽

Rodrigo Saar Gomes ◽

Jessica Cristina dos Santos ◽

Lívia Lara Pessoni ◽

Anetícia Eduarda Maldaner ◽

...

Keyword(s):

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

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Streptococcus pneumoniae Autolysis Prevents Phagocytosis and Production of Phagocyte-Activating Cytokines

Infection and Immunity ◽

10.1128/iai.00290-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 3826-3837 ◽

Cited By ~ 42

Author(s):

Anna Martner ◽

Susann Skovbjerg ◽

James C. Paton ◽

Agnes E. Wold

Keyword(s):

Streptococcus Pneumoniae ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Interleukin 12 ◽

Dependent Manner ◽

Peripheral Blood Mononuclear ◽

Exact Function ◽

Ifn Γ ◽

Dose Dependent

ABSTRACT Streptococcus pneumoniae is a major pathogen in humans. The pathogenicity of this organism is related to its many virulence factors, the most important of which is the thick pneumococcal capsule that minimizes phagocytosis. Another virulence-associated trait is the tendency of this bacterium to undergo autolysis in stationary phase through activation of the cell wall-bound amidase LytA, which breaks down peptidoglycan. The exact function of autolysis in pneumococcal pathogenesis is, however, unclear. Here, we show the selective and specific inefficiency of wild-type S. pneumoniae for inducing production of phagocyte-activating cytokines in human peripheral blood mononuclear cells (PBMC). Indeed, clinical pneumococcal strains induced production of 30-fold less tumor necrosis factor (TNF), 15-fold less gamma interferon (IFN-γ), and only negligible amounts of interleukin-12 (IL-12) compared with other closely related Streptococcus species, whereas the levels of induction of IL-6, IL-8, and IL-10 production were similar. If pneumococcal LytA was inactivated by mutation or by culture in a medium containing excess choline, the pneumococci induced production of significantly more TNF, IFN-γ, and IL-12 in PBMC, whereas the production of IL-6, IL-8, and IL-10 was unaffected. Further, adding autolyzed pneumococci to intact bacteria inhibited production of TNF, IFN-γ, and IL-12 in a dose-dependent manner but did not inhibit production of IL-6, IL-8, and IL-10 in response to the intact bacteria. Fragments from autolyzed bacteria inhibited phagocytosis of intact bacteria and reduced the in vitro elimination of pneumococci from human blood. Our results suggest that fragments generated by autolysis of bacteria with reduced viability interfere with phagocyte-mediated elimination of live pneumococci.

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